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436 TheJournalofClinicalInvestigation      http://www.jci.org      Volume 122      Number 2      February 2012

Synergy of understanding dermatologic disease and epidermal biology

John R. Stanley

University of Pennsylvania School of Medicine, Department of Dermatology, Philadelphia, Pennsylvania, USA.

Dermatologicdisease,althoughseldomlifethreatening,canbeextremelydisfiguringandinterferewiththequal-ityoflife.Inaddition,asopposedtootherorgans,justtheagingofskinanditsadnexalstructurethehairfolliclecanresultincosmeticconcernsthataffectmostofus.ThearticlesinthisdermatologyReviewSeriesdemonstraterecentprogressinunderstandingthecellbiologyandmolecularpathophysiologyoftheepidermisandhairfollicles,whichharborkeratinocyteandmelanocytestemcells.Theyrevealadynamicrelationshipbetweenresearchandclinicalcare:knowledgeofdermatologicdiseasehasfacilitatedtheunderstandingofthebiologyoftheepidermisand,inturn,progressinbasicsciencehasinformedourunderstandingofdisease.ThistypeofsynergyisaprofoundstrengthofclinicalresearchofthetypethattheJCIisdedicatedtopublishing.

IntroductionThe Reviews in this series highlight the progress in understand-ing several dermatologic diseases that are particularly important because they are common and/or disfiguring. Kubo et al. (1) high-light recent major progress in understanding the pathophysiol-ogy of atopic dermatitis (Figure 1), a disease both very common (estimates are 10%–20% prevalence in children; ref. 2) and poten-tially severe and difficult to deal with for both patients and par-ents. Myung and Ito (3) discuss recent progress in understanding the bulge of the hair follicle and its importance in harboring both keratinocyte and melanocyte stem cells. Understanding the cell biology of the bulge is important for dissecting the pathophysiol-ogy of skin cancer–like basal cell carcinoma (BCC) as well as the potentially disfiguring disease vitiligo (Figure 2). In addition, the melanocyte stem cell contributes to hair pigment. Insights into this stem cell may help us understand the physiologic process of the graying of hair with age. Normal graying of hair, although not a disease, is of great concern to millions of people, probably because pigment in hair is an indication of youth (Figure 3). Final-ly, Kasper et al. (4) and Ratushny et al. (5) discuss new aspects of the pathophysiology of skin cancers. Not only are cancers of the skin some of the most common cancers in humans, but they can be terribly disfiguring if left untreated (Figure 4).

Atopic dermatitis and the epidermal barrierOn clinical grounds alone, atopic dermatitis has been a difficult disease to understand. There is no primary skin lesion (e.g., a blister or papule) and no pathognomonic histology, issues that make mouse models of disease problematic. In general, the diag-nosis is based on a constellation of findings such as the distribu-tion of lesions, presence of pruritus, lichenification (thickening of the epidermis with accentuated skin markings) secondary to scratching, susceptibility to staphylococcal infection or colo-nization, associated atopic diseases such as allergic rhinitis or asthma,  and  certain  immunologic  abnormalities  (increased serum IgE and defects in viral cell–mediated immunity). Recent groundbreaking work on the genetics of atopic dermatitis (6) focused our attention on the epidermal barrier in this disease 

as well as other related diseases and gave impetus to the study of the epidermal barrier in immunology. This study, subsequently confirmed by many others, showed that atopic dermatitis was strongly associated with common mutations in the gene encod-ing filaggrin, a protein produced in the superficial epidermis that is thought to be important in maintaining its barrier function. Interestingly, another disease, ichthyosis vulgaris, suggested that filaggrin might be an important molecule in atopic dermatitis (7). Patients with this disease of scaly skin often have atopic der-matitis, and their histology often shows a lack of keratohyalin granules, which contain filaggrin. The genetic studies in atopic dermatitis also showed a high correlation of filaggrin muta-tions with atopic dermatitis–associated asthma, but no correla-tion with asthma not associated with atopic dermatitis. Other diseases of the epidermal barrier are also associated with atopic dermatitis. One example is Netherton syndrome, an autosomal recessive disease in which patients have ichthyosis with atopic dermatitis, allergic rhinitis, increased serum IgE, and a barrier defect (8). Genetic analysis of these patients indicates a mutation in the SPINK5 gene that encodes LEKTI, a serine protease inhibi-tor in the superficial epidermis. Patients who lack this inhibitor have excess protease activity that degrades filaggrin, among other molecules (9), resulting in a barrier defect and atopy.

In response to these novel  insights, many researchers have turned their focus to understanding the epidermal barrier, high-lighted in this series by Kubo et al. (1). This barrier is not a sim-ple barrier against water loss, but consists of at least three com-ponents. First is a liquid-liquid barrier formed by tight junctions in the epidermis. These junctions prevent paracellular diffusion of liquids around the cells of the epidermis and are located in the stratum granulosum (cells in the superficial living epider-mis that contain keratohyalin granules). The second barrier is formed by the stratum corneum at the air-liquid interface. This barrier contains keratin organized by filaggrin into compact flat sheets and contains the lipid contents of lamellar granules. This barrier presumably prevents evaporation of water from the skin surface, holds moisture in the stratum corneum, and helps block antigen access to the immune system. Finally, Langerhans cells form an immune barrier. Under conditions of stress, these cells can be activated and their dendrites extended beyond the tight junction barrier to process antigen for Th2 responses (10, 11).  

Conflictofinterest: The author has declared that no conflict of interest exists.

Citationforthisarticle: J Clin Invest. 2012;122(2):436–439. doi:10.1172/JCI62237.

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Precisely how these types of barriers, and perhaps others, con-tribute to antigen processing and diseases such as atopic derma-titis and atopic asthma remains to be determined, but presum-ably percutaneous antigen processing is intimately involved. However, present knowledge suggests that trying to maintain an intact epidermal barrier from infancy might decrease the devel-opment of atopic dermatitis.

Scarring alopecias, vitiligo, gray hair, and hair follicle stem cellsMyung and Ito (3) review the current understanding of where epi-thelial and melanocyte stem cells are located in the hair follicle. Many years of research have suggested that epithelial stem cells are present in the bulge, which is at the base of the telogen-phase (resting) hair follicle and near the arrector pili insertion of the ana-gen-phase (growing) hair follicle (12). The bulge is sometimes a theoretical anatomical area (i.e., it is not clearly apparent as a bulge anatomically), but staining of epithelial cells for stem cell markers can clearly identify their location within the hair follicle. Epithelial stem cells from the bulge area can give rise to all layers of the hair follicle each time it is regenerated from the short telogen follicle to the long anagen follicle that actively grows a hair shaft. With-out the stem cells in the bulge, the hair follicle will not regenerate (i.e., there is permanent hair loss), with the unusual exception of neogenesis of the hair follicle in mouse wounds (13). Initially it was believed that stem cells give rise to transient amplifying cells, which are then committed to produce the hair follicle. However, more detailed studies discussed in the review by Myung et al. (3) have recently suggested that stem cells may give rise to a secondary hair germ (sometimes anatomically apparent beneath the bulge in telogen hair), and that this secondary hair germ may not only give rise to cells committed to form the hair follicle but also to cells that may “reverse” to regenerate stem cells in the bulge.

Hair  pigment  comes  from  melanocytes  in  the  hair  matrix (which contains the rapidly proliferating epithelial cells that produce the hair shaft). However, these melanocytes die with the end of each hair cycle, and new melanocytes develop from mela-nocyte stem cells with each new anagen cycle. These melanocyte stem cells are also in the bulge, and recent studies have shown some of the characteristic niche requirements to maintain and activate them (14).

Various observations in disease and aging complement the above findings. For example, the importance of the keratinocyte stem cells in the bulge is underscored by the pathophysiology of scar-ring alopecia (loss of hair that does not grow back), in which the bulge is targeted by the immune system and destroyed. One very typical disease in humans resulting in scarring alopecia is lichen planopilaris. In this disease a T cell infiltrate targets the bulge and causes apoptosis of keratinocytes (15). Cutaneous lupus erythe-matosus is another inflammatory disease that causes disfiguring scarring alopecia. In these diseases, the loss of the keratinocyte stem cell is the cause of the inability to grow new hair. An example of the importance of the melanocyte stem cell is illustrated by the graying of hair with age and the disease vitiligo. Hair color is a sign of youth (Figure 3), and most elderly people lose their hair pigment (but, interestingly, not skin pigment). This physiologic loss of hair pigment is thought to be due to loss of follicular mela-nocyte stem cells (16). Finally, it is known that in vitiligo, in which an autoimmune attack on melanocytes in epidermis causes their loss, repigmentation after therapy often derives from a reservoir of melanocyte precursors in the hair follicle, presumably from stem cells in the bulge (17, 18).

Figure 1Child with severe atopic dermatitis. Such disease profoundly affects the quality of life of both the child and parents. Reproduced with per-mission from William James.

Figure 2Patient with vitiligo. This depigmenting disease is particularly dis-figuring in dark-skinned patients. Reproduced with permission from William James.

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There are important clinical (and cosmetic) implications of the above findings. For example,  if we want to permanently eliminate unwanted hair in humans (a common clinical prob-lem), we will have to eliminate the bulge, not just the matrix. Currently, electrolysis or laser hair removal does not always do this, and therefore hair often regrows. To prevent permanent hair loss in lupus or other diseases, the stem cell in the bulge must be protected from destruction. To maintain hair color, we will have to understand what niche factors in the bulge keep the melanocyte stem cell alive. Finally, to replace hair pigment for patients with vitiligo, we will have to protect the melanocyte stem cell and learn how to reactivate it to repopulate the epi-dermis. These few examples indicate the importance of under-standing the anatomically subtle, but biologically critical, bulge of the hair follicle.

Epidermal carcinogenesis: insights from human syndromes and mouse modelsA basic mouse model of skin carcinogenesis  is the multistage model  involving  initiation, promotion, and progression  (19). From this model we have learned a tremendous amount about car-cinogenesis. However, this disease, in which papillomas give rise to squamous cell carcinoma (SCC), does not really look like the most prevalent types of skin cancer in humans. In humans, skin cancer or its precursor is mostly either BCC or actinic keratosis, which is thought to be a precursor to the most common types of SCC.

BCC is the most common cancer in humans and has not, until recently, been seen in mouse models of carcinogenesis (20). Genet-ic analysis of basal cell nevus syndrome, in which patients develop hundreds of BCCs starting at a very early age, demonstrated that these patients carried mutations in the Patched 1 (PTCH1) gene (21). Loss of PTCH1 protein activates Hedgehog signaling. Fur-thermore, most sporadic BCCs in elderly patients have activat-ing mutations in this pathway (22). By genetically activating this pathway in different areas of the mouse epidermis and hair fol-licle, characteristic types (e.g., nodular, superficial) of BCCs can be produced, thus establishing mouse models that more closely mimic human BCC (23–27). As reviewed in Kasper et al. in this review series (4), the analysis of the critical importance of the Hedgehog pathway in BCC and of mouse models in which this pathway is activated in various cells and under various conditions (e.g., wounding) have led to new understandings of the molecular genetics and cell biology of this cancer as well as to new systemic and therapeutic approaches to target the Hedgehog pathway for patients with BCCs that are difficult to control.

SCC of the skin is the second most common cancer in humans, and its precursor lesion, actinic keratosis, is even more common. As discussed in the Review by Ratushny et al. (5) in this series, SCC is much more genetically complicated than BCC. Although p53 mutation is probably very important in SCC development and pro-gression, many other gene pathways have been implicated, some of which suppress p53 and some of which seem to act independently. These observations have given rise to the idea that SCC may arise by a classic multistep carcinogenesis model, in which a precursor lesion (or lesions), due to genetic instability, accrues additional mutations that drive disease progression. However, because few mouse mod-els actually demonstrate obvious actinic keratosis–like precursors before the development of SCC, the progression of this cancer, as relevant to humans, has been difficult to study. Recently, however, a transgenic mouse bearing an activated allele of the tyrosine kinase Fyn has been developed that shows typical-looking (both clinically and histologically) actinic keratosis that progresses to later-stage SCCs (28). This model should prove useful not only for studying 

Figure 3Young Vietnamese women (detail from Schoolgirls, a painting by Nguyen Vinh Binh). Their black hair indicates that these women are young, not old.

Figure 4Destructive BCC. Reproduced with permission from Christopher Miller.

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the genetic pathophysiology of development of some human SCCs but also for the study of topical agents to prevent that progression.

ConclusionThe reviews in this dermatology Review Series illustrate, in a cross-sec-tion of dermatologic diseases of the epidermis, the importance of the synergy of understanding of both human disease and basic biology to further our understanding of both in skin and its diseases. This type of synergy is representative of a basic paradigm of science that under-lies much of the science that the JCI encourages in its publication.

AcknowledgmentsThis work was supported by grant P30-AR-057217 (to the Penn Skin Diseases Research Center) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Address  correspondence  to:  John  R.  Stanley,  Department  of Dermatology, 211B Clinical Research Bldg, University Of Penn-sylvania,  415  Curie  Blvd,  Philadelphia,  Pennsylvania  19104, USA. Phone: 215.898.3240; Fax: 215.573.2033; E-mail: jrstan@ mail.med.upenn.edu.

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